Hemochromatosis is a disease of iron export dysregulation linked in most cases to the recently cloned hemochromatosis gene (HFE). Of particular interest is the transport of iron from the enterocyte and macrophage, which is excessive when HFE is defective. This competing renewal application seeks to test the hypothesis that the humoral signal reflecting both iron stores and erythropoiesis is the soluble transferrin receptor (sTfR). It is proposed that cellular reception involves HFE and that signal transduction is mediated through the membrane transferrin receptor (mTfR). Three specific aims are proposed: Aim 1: using an animal model of hemochromatosis in which the b2 microglobulin gene has been knocked out, small intestinal and bone marrow transplantation studies between (b2m -/-) and wt C57BL/6 mice will be carried out to evaluate whether cellular iron egress is disregulated due to defective cellular receptors or a defective humoral signal. Aim 2 proposes to establish an in vitro model of regulated iron egress to better study the mechanism by which HFE initiates alterations in cellular iron egress. Existing EBV transformed cells from homozygous hemochromatosis patients will be used. These cells transport iron twice as fast as control cells; the effects of transfection with HFE on this transport rate, as well as co-precipitation experiments with antibodies to HFE, will be used to evaluate their hypothesis and to directly test the sTfR as a signal molecule. In Aim 3, other forms of iron overload will be evaluated, such as porphyria cutanea tarda and African iron overload, and will be examined using EBV transformed cells and transfection of wt HFE.